WO2006038552A1 - Composition containing fine particles and process for producing the same - Google Patents

Abstract

A composition containing fine particles of a sparingly soluble drug, which is stable and is not influenced by storage environment conditions; and a process for producing the composition. The fine-particle-containing composition comprises fine particles of a sparingly soluble drug, a surfactant, and a cyclic oligosaccharide, and is characterized in that the fine particles have an average particle diameter of 50-1,000 nm. The process, which is for producing the composition containing fine particles, comprises: (I) a mixing step in which a sparingly soluble drug, a surfactant, and a poor solvent are mixed to obtain a liquid mixture; (II) a pulverization step in which the liquid mixture is pulverized with a wet disperser to obtain a dispersion of fine particles; (III) an addition step in which a cyclic oligosaccharide is added to the fine-particle dispersion; and (IV) a drying step in which the fine-particle dispersion containing the cyclic oligosaccharide is dried.

Description

 Specification

 Fine particle-containing composition and method for producing the same

 Technical field

 The present invention relates to a composition containing fine particles of a poorly soluble drug and a method for producing the same.

 Background art

 [0002] Usually, a poorly soluble drug has low solubility in water, and it is difficult to formulate it as an injection. In addition, when blended with a solid preparation, there is a problem that the bioavailability is difficult to dissolve and the bioavailability tends to be reduced. Therefore, attempts have been made to solve these problems by miniaturizing poorly soluble drugs and increasing their dispersibility in water. For example, it is known that an injection containing an anticancer agent or the like adjusted to a nano size has low toxicity and high bioavailability.

 [0003] As a method for producing fine particles of a poorly soluble drug, wet pulverization using water or an organic solvent is mainly used, and a surface modifier such as a surfactant is used during wet pulverization. This is because surfactants and the like impart electrostatic or steric repulsive force to the surface of the poorly soluble drug particles, thereby preventing the particles from aggregating in the liquid and improving the uniform dispersibility of the suspension. It is easy to maintain. In addition, a cloud point modifier is used in combination to prevent the function of the surfactant from being impaired when a suspension containing fine particles of a poorly soluble drug dispersed by a surfactant is subjected to high temperature treatment such as autoclave. Has been. For example, a combination of an ionic surfactant and an isotonic agent such as mannitol, dextrose or sodium chloride salt (see, for example, US Pat. No. 5,298,262), or a nonionic surfactant , Glycols, ethanol or a combination of cloud point modifiers such as hydroxypropyl cyclodextrin (see, for example, US Pat. No. 5,346,702). Furthermore, by limiting the particle size of poorly soluble drugs to 150-350 nm using nonionic surfactants such as pull mouth nicks and polymer substances, stable injections can be obtained even at high-temperature treatments such as autoclaves. (See, for example, JP 2002-538199 A).

[0004] On the other hand, in order to obtain a composition containing nano-sized slightly soluble drug fine particles, the suspension obtained by the above-described method for producing hardly soluble drug fine particles is further lyophilized and sprayed. Disclosed are methods of drying by fog drying or fluidized bed granulation. For example, a freeze-drying agent for injection containing sucrose as a cryoprotectant and polyvinylpyrrolidone as a surface stabilizer as essential components is disclosed by a production method using a freeze-drying method (for example, the US (See Patent No. 5,302,401).

[0005] However, in the case of a solid composition using a sugar alcohol such as mannitol or a nonionic surfactant, the desired lyophilizing agent could not be obtained. Further, as a production method using the spray drying method, a method of preparing a suspension of a HER2 inhibitor containing a hydroxypropyl cellulose and sodium deoxycholate and then spray drying is disclosed (for example, JP-A 2003- No. 26676). As a result, the drug particles in suspension and the drug particles after pulverization did not change around 900. Furthermore, in the method using fluidized bed granulation, a suspension containing 500 1500 nm fine particles is prepared using a polymer compound, a surfactant, and a saccharide as a surface modifier for drug particles, and then the suspension is prepared. A method is disclosed in which a liquid is granulated by a fluidized bed to form a solid composition (see, for example, the publication of JP 2004-175795 A).

 Disclosure of the invention

 Problems to be solved by the invention

 [0006] As described above, the technique for atomizing a poorly soluble drug is mainly applied to an injection containing a medium such as water for the purpose of improving the dispersion stability of fine particles in a liquid. It has not yet been fully examined for application to widely used solid preparations. Although the prior art considers the storage stability of fine particles in a liquid, a method and composition for producing fine particles of a poorly soluble drug focusing on the stability of fine particles in a solid composition are disclosed. Not. Specifically, in a conventional method for producing fine particles of a poorly soluble drug, the surfactant is an essential component for modifying the surface of the poorly soluble drug and improving the water dispersibility in the liquid. is there. However, in the state of being dispersed in the solid composition, the surfactant is not always necessary, but may cause adverse effects such as promoting crystal growth of drug fine particles and fusing of the fine particles.

On the other hand, pharmaceuticals are required to ensure quality such as chemical and physical stability in the distribution process. Chemical and physical changes in drugs and compositions during storage This is because not only can the drug not be used properly, but it may affect the safety of the patient being administered. Naturally, even in a composition containing fine particles of a poorly soluble drug, a change in the particle size may reduce the water dispersibility of the drug fine particles or affect the nanoavailability.

 Means for solving the problem

 [0008] As a result of investigations on the above problems, the present inventors have found that a suspension of fine particles of a poorly soluble drug wet-ground in a solution containing the poorly soluble drug and a surfactant (hereinafter referred to as By adding a cyclic oligosaccharide to the fine particle dispersion, the solid particles in the solidification process such as the drying process and after solidification can be stored even under high temperature and high humidity conditions. We have found a method for obtaining a composition in which reaggregation and crystal growth are suppressed and the size of the drug fine particles is maintained. In addition, to the fine particle-containing composition obtained by drying a fine particle dispersion of a poorly soluble drug wet-ground in a solution containing a poorly soluble drug and a surfactant, a cyclic oligosaccharide is added to a small amount of a poor solvent for the poorly soluble drug. By mixing together, the inventors have found a method for stabilizing fine particles of a poorly soluble drug in a fine particle-containing composition, and have completed the invention. These inventions are novel, in which the cyclic oligosaccharide includes a surfactant to suppress the influence of the surfactant in the solid composition on the fine particles of the hardly soluble drug, for example, dissolution and fusion. Means are disclosed.

 That is, the present invention provides:

 1. A composition comprising fine particles of a poorly soluble drug, a surfactant and a cyclic oligosaccharide, wherein the fine particles have an average particle size of 50 nm or more and lOOOnm or less,

 2. (I) a mixing step of mixing a poorly soluble drug, a surfactant and a poor solvent to obtain a mixed solution; (II) a refining step of refining the mixed solution with a wet disperser to obtain a fine particle dispersion; (I) the fine particle-containing composition according to (1) above, which is produced by a production method comprising an addition step of adding a cyclic oligosaccharide to the fine particle dispersion; and (IV) a drying step of drying the fine particle dispersion containing the cyclic oligosaccharide. object,

3. (I) A mixing step in which a poorly soluble drug, a surfactant, a poor solvent and a cyclic oligosaccharide are mixed to obtain a mixed solution. (I) The mixed solution is refined with a wet disperser to obtain a fine particle dispersion. Refinement (M) the fine particle-containing composition according to item 1 produced by a production method comprising a drying step of drying the fine particle dispersion;

 4. a mixing step of mixing a ω poorly soluble drug, a surfactant and a first poor solvent to obtain a mixed solution; (π) a refining step of refining the mixed solution with a wet disperser to obtain a fine particle dispersion; (in) a first drying step for obtaining a first mixture by drying the fine particle dispersion; (IV) a second mixture obtained by adding a cyclic oligosaccharide and a second poor solvent to the first mixture. (V) the fine particle-containing composition according to item 1 produced by a production method comprising a second drying step of drying the second mixture,

 5. The fine particle-containing composition according to any one of the preceding items 2 to 4, which is mixed as a poorly soluble drug solution in which a poorly soluble drug is dissolved in a good solvent through the mixing step,

 6. Prior to the drying step or the first drying step, the fine particles according to any one of items 2 to 5 including a concentration step of concentrating the fine particle dispersion or the fine particle dispersion containing the cyclic oligosaccharide. Containing composition,

 7. The fine particle-containing composition according to any one of items 2 to 6, wherein the drying step or the first drying step is a drying step using a spray drying method,

 8. The fine particle-containing composition according to any one of items 2 to 7, wherein the wet disperser is a homogenizer,

 9. The fine particle-containing composition according to any one of 1 to 8 above, wherein the cyclic oligosaccharide includes the surfactant.

 10. The fine particle-containing composition according to any one of claims 1 to 9, wherein the cyclic oligosaccharide is cyclodextrin,

 11. The fine particle-containing composition according to any one of items 1 to 10, wherein the surfactant is a surfactant having a hydrocarbon chain having 4 or more carbon atoms,

 12. The fine particle-containing composition according to any one of 11 and 11 in which the sparingly soluble drug is 0.1 to 40 parts by mass with respect to 100 parts by mass of the fine particle-containing composition,

 13. A solid pharmaceutical composition comprising the fine particle-containing composition according to any one of 1 to 13 above,

14. The solid pharmaceutical composition comprises tablets, granules, capsules and dry syrups The solid pharmaceutical composition according to item 13 selected from the group consisting of:

 15. (I) a mixing step of mixing a poorly soluble drug, a surfactant and a poor solvent to obtain a mixed solution;

II) Refinement of the mixed solution by a wet disperser to obtain a fine particle dispersion; (III) Addition step of adding a cyclic oligosaccharide to the fine particle dispersion; and (IV) Fine particles containing the cyclic oligosaccharide. A method for producing a fine particle-containing composition comprising a drying step of drying the dispersion;

16. (I) A mixing step in which a poorly soluble drug, a surfactant, a poor solvent and a cyclic oligosaccharide are mixed to obtain a mixed solution. (I) The above mixed solution is refined with a wet disperser to obtain a fine particle dispersion. A method for producing a fine particle-containing composition, comprising a micronization step and (III) a drying step of drying the fine particle dispersion,

 17. (I) Mixing step of mixing a poorly soluble drug, a surfactant and a first poor solvent to obtain a mixed solution, (i) Refinement of the mixed solution with a wet disperser to obtain a fine particle dispersion Process, (

III) a first drying step for obtaining a first mixture by drying the fine particle dispersion; (IV) adding a cyclic oligosaccharide and a second poor solvent to the first mixture to obtain a second mixture. (V) a method for producing a fine particle-containing composition comprising a second drying step of drying the second mixture,

 18. The method for producing a fine particle-containing composition according to any one of items 15 to 17, wherein in the mixing step, the poorly soluble drug is mixed as a poorly soluble drug solution dissolved in a good solvent.

 19. Prior to the drying step or the first drying step, the fine particles according to any one of items 15 to 18 including a concentration step of concentrating the fine particle dispersion or the fine particle dispersion containing the cyclic oligosaccharide. Production method of the containing composition,

 20. The method for producing a fine particle-containing composition according to any one of items 15 to 19, wherein the drying step or the first drying step is a drying step using a spray drying method.

21. The method for producing a fine particle-containing composition according to any one of 15 to 20, wherein the wet disperser is a homogenizer,

22. The method for producing a fine particle-containing composition according to any one of items 15 to 21, wherein in the addition step, the cyclic oligosaccharide includes the surfactant. 23. The method for producing a fine particle-containing composition according to any one of 15 to 22 above, wherein the cyclic oligosaccharide is cyclodextrin,

 24. The method for producing a fine particle-containing composition according to any one of 15 to 23, wherein the surfactant is a surfactant having a hydrocarbon chain having 4 or more carbon atoms,

 25. The method for producing a fine particle-containing composition according to any one of 15 to 24 above, wherein the hardly soluble drug is 0.1 to 40 parts by mass with respect to 100 parts by mass of the fine particle-containing composition.

 The invention's effect

 [0010] According to the present invention, in a technique for atomizing a poorly soluble drug by wet pulverization using a surfactant, a suspension containing fine particles of the poorly soluble drug is dried by further using a cyclic oligosaccharide. Also in the composition after the process and after drying, the aggregation and crystal growth over time of the fine particles of the hardly soluble drug can be suppressed. Further, according to the present invention, it is possible to provide a fine particle-containing composition in which fine particles of a hardly soluble drug are physically present without being affected by the storage environment such as temperature and humidity. Therefore, according to the present invention, it is possible to simply blend fine particles of a poorly soluble drug into tablets and capsules that are widely used in oral preparations, or time-adjustable dry syrups that can be redispersed in water. it can. Furthermore, according to the present invention, since a poorly soluble drug can be orally administered while maintaining the size as fine particles, absorption of the poorly soluble drug is promoted, bioavailability is increased, or the amount of drug is reduced. Can provide a pharmaceutical composition with excellent compliance. Furthermore, since the fine particle-containing composition of the present invention or a pharmaceutical composition containing the same is excellent in storage stability, it can be transported and distributed as a premix raw material for pharmaceuticals or as a pharmaceutical and can be widely spread immediately. .

 BEST MODE FOR CARRYING OUT THE INVENTION

 The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

The fine particle-containing composition according to the present invention is a composition in which fine particles of a poorly soluble drug are contained in a solid phase. The fine particle-containing composition according to the present invention is a poorly soluble drug, a surface activity. Including an agent and a cyclic oligosaccharide, fine particles of a poorly soluble drug are dispersed in the composition. In addition, the composition may contain additives such as other saccharides and polymer substances as necessary. The fine particle-containing composition according to the present invention is prepared by adding arabic acid cyclic oligosaccharide to a fine particle dispersion containing fine particles of a poorly soluble drug that has been wet-pulverized in a liquid containing a poorly soluble drug and a surfactant, followed by drying. You can get it from Yuko. Further, the cyclic oligosaccharide may be used by mixing with a poorly soluble drug or a surfactant before wet grinding. Furthermore, the composition containing the fine particle of the poorly soluble drug and the surfactant obtained by drying the finely dispersed fine particle dispersion of the poorly soluble drug wet-milled in the solution containing the poorly soluble drug and the surfactant is further added to the cyclic oligo. The fine particle-containing composition according to the present invention can also be obtained by adding sugar and a small amount of a poor solvent, mixing and drying. In these production methods, some or all of the cyclic oligosaccharide and the surfactant form an inclusion body, so that the physics of the fine particles of the poorly soluble drug in the drying process or the preservation of the fine particle-containing composition. Contributes to stability.

 [0013] The fine particles of the present invention are nano-sized particles having an average particle diameter of 1 μm or less, and are also called so-called nanoparticles, and the average particle diameter can be measured using a light scattering method. For example, an instrument capable of measuring a nanometer-sized particle size by mixing a composition containing a fine particle of a poorly soluble drug and a poor solvent, dispersing the fine particle of the poorly soluble drug, and diluting as necessary. For example, it can be measured with a dynamic light scattering photometer DLS-7000 of Otsuka Electronics Co., Ltd. or a laser zeta electrometer ELS-8000. Similarly, the fine particles of the poorly soluble drug in the fine particle dispersion can be appropriately diluted and measured with a poor solvent for the poorly soluble drug. The average particle diameter of the slightly soluble drug fine particles in the present invention, when measured by dispersing the solid dispersion in water by the light scattering method, is lOOOnm, preferably 900 nm, more preferably 800 nm. . The lower limit of the average particle diameter is not particularly limited, but is 50 nm, preferably lOOnm, more preferably 200 nm. Therefore, the average particle size of the hardly soluble drug fine particles in the present invention is 50 nm to 1 OOOnm, preferably 100 ηm to 900 nm, more preferably 200 nm to 800 nm.

In the present invention, the drug includes a therapeutic agent or a diagnostic agent. The therapeutic agent may be a pharmaceutical containing a biological compound such as a synthetic compound, protein, and peptide, or a diagnostic agent Is an X-ray contrast agent or other diagnostic drug. The drug is preferably poorly soluble and dispersible in at least one liquid medium. Here, sparingly soluble means the solubility of a drug in a solvent in terms of Japanese pharmacopoeia 14 (hereinafter referred to as JP) or US pharmacopoeia 24 (hereinafter USP). It indicates a state of “difficult”, “extremely difficult to dissolve”, or “almost insoluble”. Specifically, according to the Japanese Pharmacopoeia, when the drug is solid, the solubility is 30% when it is powdered and placed in a solvent and shaken vigorously every 5 minutes at 20 ± 5 ° C for 30 seconds. Degree of dissolution within minutes. “Undissolved” means that the amount of water required to dissolve drug lg is more than SlOOmL and less than lOOOmL. In addition, “extremely insoluble” means that the amount of water required to dissolve the drug lg is more than lOOOmL and less than lOOOOmL, and “almost insoluble” means the amount of water required to dissolve the drug lg. Indicates that it is 1000 OmL or more. In the present invention, preferably, the poorly soluble drug is a drug that is “extremely insoluble” or “almost insoluble” in terms of solubility in water, that is, the amount of water required to dissolve the drug lg is at least lOOOmL. It is a certain drug. Preferably, the poorly soluble drug is a drug that is “almost insoluble” in terms of solubility in water, that is, a drug that has an amount of water of more than OOOOmL to dissolve the drug lg.

 [0015] The poorly soluble drug of the present invention is not particularly limited, and examples thereof include steroid agents, enzyme inhibitors, analgesics, antifungal agents, cancer therapeutic agents, antiemetics, analgesics, cardiovascular agents, Anti-inflammatory agent, anthelmintic agent, antiarrhythmic agent, antibiotics (including penicillin), anticoagulant agent, antidepressant, antiglycemic agent, antiepileptic agent, anti-dementia agent, antihistamine, antihypertensive agent, antimuscarin Agents, antimycobacterial agents, antineoplastic agents, immunosuppressive agents, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, β-adrenergic receptor blockers, blood Formulations and substitutes, cardiotonic agents, contrast agents, corticosteroids, antitussives (descending and mucolytic agents), diagnostic agents, diagnostic contrast agents, diuretics, dopaminergic agents (antiparkinsonian agents), hemostatic agents, Immune agent, lipid regulator, muscle relaxant, prostagland , Radiopharmaceuticals, hormones, anti-allergic agents, stimulants and anorectic agent, a sympathomimetic agent, thyroid agent, a blood tube expansion agent can be selected from a variety of drugs. These poorly soluble drugs can be used alone or in combination of two or more.

[0016] The amount of the poorly soluble drug in the fine particle-containing composition is 100% of the fine particle-containing composition. The amount is 0.1 to 40 parts by weight, preferably 0.5 to 35 parts by weight, more preferably 1 to 30 parts by weight, and still more preferably 1 to 25 parts by weight with respect to parts by weight. .

 [0017] The surfactant of the present invention is used together with a poorly soluble drug when miniaturizing a poorly soluble drug, and has an effective role in miniaturizing the poorly soluble drug. Alternatively, when the fine particle-containing composition according to the present invention is redispersed in a solvent such as water, it has a role of uniformly dispersing fine particles of a poorly soluble drug. Therefore, as long as it has surface active ability, it is not particularly limited, but preferably has a high HLB surface activity capable of improving the water dispersibility of fine particles of poorly soluble drugs, for example, HLB of 8 or more, preferably Is a surfactant having an HLB of 10 or more, more preferably an HLB of 12 or more.

[0018] The surfactant of the present invention is not particularly limited as long as at least a part of the surfactant can be included in cyclodextrin. For example, it is a surfactant having a hydrocarbon chain, and the hydrocarbon chain is not particularly limited to a straight chain, a branched chain, or a ring, and for example, a nonionic surfactant having a hydrocarbon chain, an ionic interface Activators and natural surfactants. Preferably, the surfactant of the present invention is a surfactant having a hydrocarbon chain having 4 or more carbon atoms, more preferably 6 or more, still more preferably 8 or more, and particularly preferably a hydrocarbon chain having a carbon number. 10 or more surfactants. Specific examples of the surfactant are shown below, but are not limited thereto. Nonionic surfactants include glyceryl monostearate, sorbitan fatty acid ester, decaglyceryl monomyristic acid, polyglycerin fatty acid esters such as hexaglyceryl monolaurate and glyceryl monooleate (Nikko Chemicals Corporation), sucrose fatty acid Esters (Mitsubishi Kaisei Foods Co., Ltd.), polyoxyethylene castor oil derivatives (CO series (registered trademark), Nikko Chemicals Co., Ltd.), polyoxyethylene hydrogenated castor oil (eg HCO series (registered trademark), Nikko Chemicals) Co., Ltd.), monococo oil fatty acid polyoxyethylene sorbitan, polysorbate 80 (trade name Tween 80 etc.), polysorbate 20 (trade name Tween 20 etc.) and other polyoxyethylene sorbitan fatty acid esters, lauromacrogol and polyoxyethylene (20) cetyl Polyoxyethylene alkyl ethers (Nikko Chemicals Co., Ltd.) such as ether, polyoxyethylene (15) oleyl ether, polyoxyethylene (20) Polyoxyethylene (4) Polyoxyethylene polyoxypropylene such as cetyl ether Alkyl ether (Nikko) Chemicals Co., Ltd.), polyethylene glycol monostearate, polyethylene glycol distearate and polyethylene glycol monooleate (Nikko Chemicals Co., Ltd.). Examples of ionic surfactants include fatty acid sarcophagus, sodium stearoyl lactate, acyl lactate such as calcium stearoyl lactate, alkyl sulfates such as sodium dodecyl sulfate (Wako Pure Chemical Industries, Ltd.), alkyl phosphate, Benzalkol chloride, cetylpyridium chloride, and the like. Natural surfactants include soybean lecithin (Tsuruichi Lecithin Industry), hydrogenated soybean phospholipid (Tsuruichi Lecithin Industry Co., Ltd.), egg yolk lecithin (Cupiichi Co., Ltd.), lysolecithin (Kyowa Hakko Kogyo Co., Ltd.), water Examples include lecithins such as acid lecithin (Nikko Chemicals Co., Ltd.) and cholates such as sodium cholate and sodium deoxycholate. These surfactants may be used alone or in combination of two or more. Preferred are alkyl sulfate ester salts, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyglycerin fatty acid esters, and more preferred are alkyl sulfate ester salts, sucrose fatty acid esters, polysorbate 80, and polysorbate 20. is there.

 [0019] The cyclic oligosaccharide used in the present invention is not particularly limited as long as it has a function of enclosing a surfactant. For example, the cyclic oligosaccharide having 4 to 12 glucose unit forces is also available. Cyclic lacto-oligosaccharides with sugar and lactose unit strength, preferably <<-cyclodextrin (Nippon Food Processing Co., Ltd.), β-cyclodextrin (Nippon Food Processing Co., Ltd.), y-cyclodextrin (Nippon Food Processing Co., Ltd.) Company) and cyclic tetrasaccharide (Hayashibara Biochemical Laboratories Co., Ltd.), more preferably α-cyclodextrin, j8-cyclodextrin, and γ-cyclodextrin. These cyclic oligosaccharides can be used alone or in combination of two or more.

 [0020] The relative amounts of the poorly soluble drug, the surfactant and the cyclic oligosaccharide in the fine particle-containing composition according to the present invention are not particularly limited, and may contain other components. For example

The compounding ratio of the cyclic oligosaccharide to 1 part by mass of the poorly soluble drug in the fine particle-containing composition is 0.5 to: LOOO parts by mass, preferably 1 to 500 parts by mass, more preferably 2 to 200 parts by mass. More preferably 3 to: LOO parts by mass. Also, in the fine particle-containing composition The compounding ratio of the surfactant to 1 part by mass of the poorly soluble drug is 0.1 to 10 parts by mass, preferably 0.2 to 5 parts by mass, more preferably 0.2 to 2 parts by mass, and further preferably 0. 4 to 1 mass part.

 [0021] The method for producing a fine particle-containing composition according to the present invention comprises a step of making a sparingly soluble drug fine particles in the presence of a surfactant, a step of adding a cyclic oligosaccharide, and drying a fine particle dispersion. Includes a drying step. By including an addition step of adding a cyclic oligosaccharide, the surfactant used in the miniaturization step, that is, a surfactant adsorbed on the surface of a free surfactant or a poorly soluble drug is included. As a result, during the drying step or in the composition after drying, aggregation of fine particles of the poorly soluble drug and crystal growth of the poorly soluble drug due to the presence of the surfactant can be suppressed. Therefore, the method for producing the fine particle-containing composition of the present invention can be exemplified by the following embodiments.

 (First embodiment according to the present invention)

 FIG. 1 is a diagram for explaining the procedure of the first embodiment of the method for producing the fine particle-containing composition of the present invention. This embodiment is characterized by adding a cyclic oligosaccharide to a fine particle dispersion after making a sparingly soluble drug fine. That is, in the mixing step (I), a poorly soluble drug, a surfactant and a poor solvent are mixed to obtain a mixed solution. Next, (ii) in the refinement step, the mixed solution is refined with a wet disperser to obtain a fine particle dispersion. Further, in the (III) addition step, the cyclic oligosaccharide is added to and mixed with the fine particle dispersion, and then (IV) the fine particle dispersion containing the cyclic oligosaccharide is dried in the first drying step. A particle-containing composition can be obtained.

 (Second embodiment according to the present invention)

FIG. 2 is a diagram for explaining the procedure of the second embodiment of the method for producing a fine particle-containing composition according to the present invention. This embodiment is characterized in that a sparingly soluble drug is miniaturized in the presence of a cyclic oligosaccharide. That is, in the (I) mixing step, a poorly soluble drug, a surfactant, a cyclic oligosaccharide and a poor solvent are mixed to obtain a mixed solution. Next, (ii) by the micronization step, the liquid mixture containing the cyclic oligosaccharide is micronized by a wet disperser to obtain a microparticle dispersion of the sparingly soluble drug. Further, (i) the fine particle-containing composition of the present invention can be obtained by drying the fine particle dispersion containing the cyclic oligosaccharide by a drying step. (Third embodiment according to the present invention)

 FIG. 3 is a diagram for explaining the procedure of the third embodiment of the method for producing a fine particle-containing composition according to the present invention. This embodiment is characterized in that after obtaining a composition containing fine particles of a poorly soluble drug and a surfactant, a cyclic oligosaccharide and a poor solvent are added and mixed. That is, in the mixing step (I), a poorly soluble drug, a surfactant, and a first poor solvent are mixed to obtain a mixed solution. Next, in the (II) refinement step, the mixed solution is refined with a wet disperser to obtain a fine particle dispersion. Further, (III) in the first drying step, the fine particle dispersion is dried to obtain a mixture (hereinafter referred to as a first mixture) containing the fine particles of the hardly soluble drug and the surfactant. Subsequently, in the (IV) addition step, the cyclic oligosaccharide and the second poor solvent are added to the first mixture and mixed to obtain a mixture (hereinafter referred to as the second mixture). Furthermore, in order to remove the second poor solvent, (V) as the second drying step, the second mixture can be dried to obtain a fine particle-containing composition. Here, the first poor solvent and the second poor solvent may be the same or different. Further, in the step of obtaining the first mixture or the second mixture, other saccharides or polymer substances may be used. The method of the second drying step is not particularly limited as long as the second poor solvent can be removed.

 (Fourth embodiment according to the present invention)

In the micronization step of the present invention, a wet disperser such as a homogenizer or a mill and a dispersion technique using a surfactant are used. Preferably, a method based on a crystallization technique can be further combined. For example, as shown in FIG. 4, it can be combined with the first embodiment. That is, after the mixing step of mixing a surfactant and a poor solvent to obtain a mixed solution as a poorly soluble drug solution in which a poorly soluble drug is dissolved in a good solvent, the mixed solution is refined with a wet disperser, and a fine particle dispersion It is a manufacturing method including the refinement | miniaturization process of obtaining. Here, the surfactant or the cyclic oligosaccharide is desirably dissolved and dispersed in advance in a poorly soluble drug solution or a poor solvent. Further, it is preferable to add a concentration step prior to the drying step in order to remove the good solvent or further remove the poor solvent. Specifically, with respect to the fine particle dispersion containing the cyclic oligosaccharide, the fine solvent can be concentrated by removing the good solvent and the poor solvent using an ultrafiltration method or a dialysis method, and then dried. The fine particle-containing composition of the present invention can be obtained by the drying step. As in the first embodiment, in the second or third embodiment, by including these crystallization techniques and concentration steps, finer fine particles can be obtained, and the effects of the present invention can be obtained. Can be increased.

 [0026] Furthermore, as a method for producing the fine particle-containing composition according to the present invention, the first, second or fourth embodiment may be combined with the third embodiment. For example, after obtaining the fine particle-containing composition of the present invention according to the first embodiment, an addition step of adding and mixing a cyclic oligosaccharide and a second poor solvent, and removing the second poor solvent A second drying step may be added. Alternatively, an addition step of adding and mixing a cyclic oligosaccharide and a poor solvent to a composition containing a slightly soluble drug fine particle and a surfactant obtained in advance by another method and removing the added poor solvent You can add the drying process! The embodiments of the present invention are not limited to these.

 In the mixing step of the present invention, prior to the micronization step of the present invention, a poorly soluble drug, a surfactant and a poor solvent are mixed, and if necessary, a cyclic oligosaccharide or other additive is further mixed. This is a step of obtaining a mixed solution. In order to obtain fine particles with good efficiency in the next miniaturization step, the mixed solution is preferably in a state where the components are uniformly mixed. Therefore, in the mixing step, various operations can be performed to disperse the particles of the poorly soluble drug, to disintegrate the drug powder, or to modify the surface of the drug powder. For example, in operations such as stirring of the mixed liquid and pulverization of the drug powder, a propeller stirrer, Homodisno (Mizuho Industry Co., Ltd.), Homomixer (Mizuho Industry Co., Ltd.), Homojetter (Special Machine Industry Co., Ltd.), In addition to a pressure emulsifier, a colloid mill (Special Machine Industries Co., Ltd.), a jet mill (Kurimoto Kyosho Co., Ltd.), a grinder, etc., a wet disperser used in the micronization process can be used as appropriate. For example, the poorly soluble drug may be used after being coarsely pulverized with a jet mill or an attritor in the form of powder and mixed with a surfactant, a poor solvent or the like with a homomixer. Alternatively, the poorly soluble drug and the surfactant may be kneaded or mixed with an attritor or mill, and then added with a solvent and refined with the wet disperser of the present invention.

[0028] In the fine particle dispersion process of the present invention, a surfactant is used as a technique for dispersing a poorly soluble drug, and a wet disperser is used in combination. That is, in the mixed solution obtained in the mixing step of the present invention, That is, this is a step of obtaining a fine particle dispersion containing fine particles of a poorly soluble drug by refining the poorly soluble drug with a wet disperser in a solution containing the poorly soluble drug and a surfactant. The concentration of the surfactant in the mixed solution at the time of miniaturization is not particularly limited, but is usually 0.01 to 5 w / v%, preferably 0.1 to 4 w / v%, more preferably 0. 3 to 3 w / v%.

 [0029] When a crystallization technique is further used in the miniaturization step of the present invention, in the mixing step of the present invention, a mixing step of mixing a poorly soluble drug solution in which a poorly soluble drug is dissolved in a good solvent and a poor solvent, Fine particles of poorly soluble drug can be precipitated. At this time, the surfactant used in the mixing step can be used as a poor solvent, a good solvent, or added to both. Moreover, when using a crystallization technique, it is preferable to use a wet disperser immediately after the mixing step. That is, after the mixing step, a fine particle dispersion of a poorly soluble drug is prepared by carrying out fine processing with a wet disperser usually within 5 minutes, preferably within 3 minutes, more preferably within 1 minute.

 [0030] The good solvent in the present invention is a solvent that completely dissolves a poorly soluble drug, and is not particularly limited. For example, a good solvent such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, etc. Examples thereof include ketones such as alcohol, acetone and methylethylketone, acetonitrile, dioxane, methyl ether, chloroform, and mixed solvents thereof. Further, the poor solvent in the present invention is a solvent that hardly dissolves a poorly soluble drug and is not particularly limited, and examples thereof include water, acidic water to which various acids are added, and basic water to which various bases are added. . When the crystallization technique is used, the poor solvent is preferably a solvent miscible with the drug solution dissolved in the good solvent. When a poorly soluble drug solution dissolved in a good solvent is mixed with the poor solvent, the mixing ratio thereof is not particularly limited as long as it causes the precipitation of the drug, but the amount of the good solvent is based on the poor solvent. Usually, 0.001 to 50 v / v%, preferably 0.01 to: LOv / v%, more preferably 0.01 to 5 v / v%.

[0031] The wet disperser used in the micronization step of the present invention is not particularly limited as long as it has an ability to make a hardly soluble drug into the fine particles of the present invention. The mill can be miniaturized by compressing or shearing by rotation of beads, balls, rings or rollers. For example, the trade name Dynomill (WA Bachofen, Switzerland), ball mill (Flitch) , Germany), trade name Micros (Nara Machinery Co., Ltd.), supermarket mill mill (Nara Machinery Co., Ltd.), and dry rice beads mill (DRAISWERKE USA). The mechanism of the homogenizer is not particularly limited as long as it is a device capable of realizing a shearing force, an impact force, a cavity force, a high-speed flow rate, an ultrasonic wave and the like that can make fine particles of a poorly soluble drug fine. For example, a high-pressure homogenizer that collides treatment liquids or penetrates a minute orifice, a high-speed rotation type homogenizer that uses shearing force or cavity force due to minute clearance such as a rotor or stator screen, or an ultrasonic homogenizer Homogenizer. The high-pressure homogenizer includes the product name Nanomizer 1 (Yoshida Kikai Kogyo Co., Ltd.), the product name Microfluidizer 1 (MFI, USA), the piston gap homogenizer 1 (Product name EmulsiFlex-C160, Avestin Inc. Canada), APV type Homogenizer (Invensys Systems Co., Ltd.), trade name Clearichi SS5 (EM Technique Co., Ltd.), Losoavi homogenizer 1 (Doei Shoji Co., Ltd.), trade name Ultimateizer 1 (Sugino Machine Co., Ltd.), etc. The powers listed are not limited. High-speed rotating homogenizers include high-performance dispersion emulsifiers (trade name Claremix, Em'Technique Co., Ltd.), trade name Polytron homogenizer I (KINEMATICA), trade name Hiscotron (Microtech-Thion Co., Ltd.), etc. It is done. Examples of the ultrasonic homogenizer include a high-efficiency ultrasonic homogenizer (Nihon Sibel Hegner). The wet disperser of the present invention is preferably a homogenizer, and more preferably a high-pressure homogenizer.

When a high-pressure homogenizer is used as the wet disperser of the present invention, the pressure at the time of miniaturization is not particularly limited because it depends on the capacity of the apparatus. However, when other dispersion technology is not used, it is usually 14000 psi to 60000 psi, preferably Is 20000 psi to 60000 psi, more preferably 30000 psi to 60000 psi. When combined with crystallization technology, etc., the pressure at the fine pressure of the high-pressure homogenizer is surprisingly lower, usually 500-40000 psi, preferably 1000-30000 psi, more preferably 3000-30000 psi. In addition, the temperature of the liquid at the time of micronization by the high-pressure homogenizer according to the present invention is not particularly limited, but is usually a temperature at which a poorly soluble drug is not completely dissolved in the solvent, and the lower limit is the solidification or viscosity of the solvent. It is a temperature that does not cause a flickering, specifically 1-40 ° C. Particularly preferably 1-30 ° c. Furthermore, the number of passes is not particularly limited in the miniaturization with a high-pressure homogenizer.

The target fine particles can be obtained by continuously performing in-line method.

 [0033] When a high-speed rotating homogenizer is used as the wet disperser of the present invention, the rotational speed at the time of miniaturization is usually 12000 rpm or higher, preferably 15000 rpm or higher, more preferably 18000 rpm or higher. Further, the temperature of the liquid to be treated at the time of this treatment is not particularly limited, but is usually a temperature at which the poorly soluble drug is not completely dissolved in the solvent, and the lower limit is a temperature at which the solvent does not solidify or become viscous, Specifically, it is 1 to 40 ° C, preferably 1 to 30 ° C.

 [0034] When a mill is used as the wet disperser of the present invention, a method for preparing a fine particle dispersion is a step of rough-treating a poorly soluble drug in a solution containing a surfactant and then attriting in the presence of a grinding medium. including.

 [0035] The adding step of the present invention is a step of adding and mixing a cyclic oligosaccharide, and is intended to include a surfactant in the cyclic oligosaccharide. At this time, the cyclic oligosaccharide may be added after being dissolved or dispersed in a poor solvent for a poorly soluble drug, such as water, if necessary. The mixing method is not particularly limited as long as it can be mixed so that the surfactant and the cyclic oligosaccharide can come into contact with each other. For example, a stirring operation or apparatus in the mixing process can be used. As in the third embodiment, when adding cyclic oligosaccharide to the first mixture containing the slightly soluble drug fine particles and the surfactant, the second poor solvent is added and mixed. The second poor solvent may be the same as or different from the first poor solvent used in the mixing step. The second mixture obtained by adding the second poor solvent is not particularly limited, and the addition method of the second poor solvent is not particularly limited. May be liquid, pasty, or wet powder. Preferably, in the addition step of the third embodiment, the second poor solvent is added together with the cyclic oligosaccharide to the first mixture obtained by the first drying step as a Noinder liquid in so-called wet granulation. be able to. By drying the granulated product, the fine particle-containing composition according to the present invention can be obtained.

[0036] The drying step of the present invention is a step of drying the fine particle dispersion or the second mixture, and the good solvent and the poor solvent contained therein can be removed. These drying processes For example, the ability to use a known method such as a spray drying method, a fluidized bed granulation method, a freeze drying method or a shelf drying method alone or in combination of a plurality of methods is not limited to these. In the spray drying method, the fine particle-containing composition can be obtained by spraying the fine particle dispersion of the present invention with a spray dryer or the like and drying it. The inflow air temperature at the time of spray drying is usually 80 ° C to 200 ° C or higher, preferably 90 ° C to 180 ° C, more preferably 100 ° C to 160 ° C. Further, the solid content concentration of the fine particle dispersion during spray drying is, for example, 0.5 to 30%, preferably 1 to 20%, more preferably 3 to 15%. Here, the solid content concentration refers to the total concentration of components that do not volatilize in each drying step in the dispersion, that is, poorly soluble drugs, surfactants, cyclic oligosaccharides, other excipients, and the like. In the fluidized bed granulation method, a fine particle-containing composition is obtained by spraying the fine particle dispersion of the present invention onto powder such as lactose or starch and granulating the powder. In the freeze-drying method, an isotonic agent such as a saccharide is added to the fine particle dispersion, and then it is usually frozen at 20 ° C to 60 ° C using a freeze dryer to remove the solvent and dry. Thus, a fine particle-containing composition can be obtained. In the shelf-type drying method, the fine particle dispersion is used as it is, or after further adsorbing a solvent to an excipient, it is usually dried at 50 ° C. to 80 ° C. to obtain a fine particle-containing composition. The drying step of the present invention or the first drying step in the third embodiment is preferably a spray drying method, a freeze drying method or a fluidized bed granulation method, more preferably a spray drying method. After spray drying, secondary drying may be further performed using a fluidized bed apparatus or shelf drying. In the second drying step in the third embodiment, a drying method can be selected according to the amount of the second poor solvent added, that is, according to the properties of the second mixture. For example, if the second mixture is liquid, a method similar to the method for drying the fine particle dispersion can be used. In the case of a wet powder, a fluidized bed granulation method can be used. In the drying step of the present invention, an adsorption method for silicic anhydride or the like can be used in combination, and solidification may be performed using a method other than the above. In the drying step of the present invention, additives such as excipients and binders necessary for the powder used in a known method may be blended. However, since the addition of cyclic oligosaccharides can improve the physical stability of the fine particles of poorly soluble drugs, it is not necessary to add these additives more than necessary. Therefore, since a composition containing a high content of hardly soluble drug fine particles can be obtained rather than the hardly soluble drug concentration in the final pharmaceutical preparation, It can be applied to Eve's solid pharmaceutical composition.

[0038] The microparticle-containing composition according to the present invention can be administered to humans and animals by oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracapsular, transvaginal, intraperitoneal, topical, or oral or nasal injection. Can be given.

 [0039] Pharmaceutical compositions for various administrations can be further prepared using the fine particle-containing composition according to the present invention. Examples of the pharmaceutical composition of the present invention include tablets, powders, fine granules, granules, force capsules, pills, dry syrups, troches, solutions, suspensions, emulsions, elixirs, syrups, troches, etc. Oral administration of inhalants, suppositories, injections, ointments, patches, patches, eye ointments, eye drops, nasal drops, ear drops, lotions, etc. Can be administered. At this time, as the fine particle-containing composition, two or more kinds of fine particle-containing compositions having different kinds and concentrations of poorly soluble drugs may be used.

 [0040] As the pharmaceutical composition of the present invention, the fine particle-containing composition may be used as it is, but a pharmacologically acceptable additive can be used. In the case of a solid pharmaceutical composition, commonly used excipients, binders, disintegrants, lubricants, coloring agents, coating agents and the like can be used. Then, these additives can be blended to prepare a solid pharmaceutical composition by a known method, that is, by combining operations such as mixing, granulation, compression, tableting, and capsule filling.

[0041] An injection is prepared by adding the solubilizing agent, isotonic agent, stabilizer, soothing agent, buffer, suspending agent, antioxidant to the fine particle-containing composition according to the present invention as necessary. Add to the above and make the drug product by the conventional method. In the case of an injection, it can be a freeze-dried agent. Injectables should be sterilized by high-pressure heat for at least 8 minutes at 121 ° C, for example. Injectables can also be administered intravenously, intradermally, subcutaneously, or intramuscularly. The injection of the present invention is preferably an injection prepared at the time of use. When using the injection preparation, the strength of using the fine particle-containing composition of the present invention as it is or an isotonic agent such as sucrose, glucose, D-mannitol, sodium chloride, etc. may be added. For example, a microparticle-containing composition obtained by adding these isotonic agents to a dispersion of a sparingly soluble drug as necessary and drying by freeze-drying is used as an injection for use at the time of use. be able to.

[0042] The external preparation of the present invention includes a base material, an emulsifier, a thickener, Ointments, creams, suppositories, patches, lotions and the like can be produced by adding conventional preservatives and stabilizers and the like. Alternatively, it can be prepared as a ready-to-use lotion as in the case of injections. As the base material to be used, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, etc. can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, Examples include fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, and purified water. Oxidizing agents, chelating agents, preservatives, colorants, fragrances and the like can be added.

Specific examples of additives used in the pharmaceutical composition of the present invention include, for example, excipients such as D-manntol, lactose (including anhydrous lactose), sucrose (including purified sucrose), sodium bicarbonate Corn starch, potato starch, wheat starch, rice starch, partially alphalated starch, crystalline cellulose, light anhydrous key acid, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate, precipitated calcium carbonate, key acid Examples of binders such as calcium include povidone, dextrin, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, sodium canoloxymethylcellulose, alpha-unified starch, sodium alginate, pullulan, and arabia gum powder. But, The present invention is not limited to these. Lubricants include hardened oil, hardened castor oil, stearic acid, magnesium stearate, calcium stearate, behenic acid glyceride, sodium stearyl fumarate, etc., low substituted hydroxypropylcellulose as disintegrant, Carmellose, sodium carboxymethyl starch, crospovidone and the like may be added, but are not limited thereto. Further, the coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethinoresenorerose, hydroxypropinoremethinoresenorelose phthalate, canoleoxy methinorenoresenorerose, canolemellose sodium, canolemellose Cellulose derivatives such as potassium, cenololose acetate and cellulose acetate phthalate, ethyl acrylate acrylate methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD , Methacrylic acid copolymer S, 2-Methyl-5-Burpyridine methyl acrylate , Dimethylaminoethyl metaatalylate 'attaric acid polymers such as methyl metaatalylate copolymer, polybulurpyrrolidone, polybulassal jetylaminoacetate, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol, macrogol Synthetic polymer materials such as flavour, polysaccharides such as pullulan and chitosan, and natural polymer materials such as gelatin, sorghum gelatin, gum arabic and shellac. Plasticizers include dioctyl adipate, triethyl taenoate, triacetin, glycerin, concentrated glycerin, propylene glycol, etc., as a suspension or emulsifier, lecithin, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene cured Castor oil, polysorbate, polyoxyethylene 'polyoxypropylene copolymer, etc., as a flavoring agent such as menthol, brackish oil, lemon oil, orange oil, etc., as antioxidant, sodium ascorbate, L-cysteine , Sodium sulfite, natural vitamin E, and other sugar coatings such as sucrose, lactose, starch, precipitated calcium carbonate, gum arabic, carnauba wax, shellac, beeswax, macrogol, ethylcellulose, methylcellulose, povidone, etc. As the key acid Gnesium, light anhydrous caustic acid, hydrogenated oil, stearic acid, magnesium stearate, paraffin, castor oil, macrogol, butyl acetate, cellulose acetate phthalate, polybutylacetal, jetylaminoacetate, shellac, etc. As hydrogels, hydrous diacid oxide, light anhydrous caustic acid, heavy anhydrous caustic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminate hydroxide, magnesium aluminate metasilicate, stearic acid, calcium stearate , Magnesium stearate, tricalcium phosphate, talc, corn starch, etc., and coloring agents include food yellow 4, food yellow 5, food red 2, food red 102, food blue 1, food blue Tars such as No. 2 (Indigo Carmine) and Food Yellow No. 4 Aluminum Lake Dyes, yellow ferric oxide, thirty-two Sani 匕鉄 (red iron oxide)

, Black iron oxide, titanium oxide, zinc oxide, talc, turmeric extract, caramel, carotene solution, β-carotene, copper chlorophyll, copper chlorophyllin sodium, riboflavin, carbon black, medicinal charcoal and the like. Solvents include water, ethyl alcohol, isopropyl alcohol, ethyl acetate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butylene glycol, dimethylformamide, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil , Sesame oil, glycerin, polyethylene glycol The power that can be used is not limited to these.

[0044] Specifically, the fine particle-containing composition according to the present invention can be prepared by the following method. 10.5mg / mL Sodium dodecyl sulfate (Wako Pure Chemical Industries, Ltd., abbreviated as SDS) in 200mL / mL 200mg / mL glibenclamide (4- [2- (5-Chloro-2-methoxybenzoylamino) ethyl] ( N-cyclohexylcarbamoyl) benzene-sulfonamide ^ Well dissolved in water 、, Wako Pure Chemical Industries, Ltd. (hereinafter abbreviated as Daribenclamide) in 2 mL of dimethylsulfoxide (Wako Pure Chemical Industries, Ltd., hereinafter abbreviated as DMSO) In addition, after stirring, the mixture is immediately put into Nanomizer 1 (Yoshida Kikai Kogyo Co., Ltd., hereinafter abbreviated as Nanomizer 1) and treated for lOmin to obtain a fine particle dispersion. DMSO is removed by dialysis treatment of the above dispersion using an lOmg / mL SDS aqueous solution to obtain a concentrated microparticle dispersion. 17.5 mg of α-cyclodextrin (Nippon Food Processing Co., Ltd., hereinafter abbreviated as a-CD) and 12.5 mL of purified water are mixed per 7.5 m of this fine particle dispersion A. This solution is spray-dried using a spray dryer Pulvis Mini-Spray GB22 (Yamato Scientific Co., Ltd., hereinafter abbreviated as S.D.-GB22) to obtain a solidified fine particle-containing composition. The fine particle-containing composition prepared by this method can be used as granules, tablets or capsules by mixing with excipients, disintegrants, lubricants, etc., and then granulating, tableting or capsule filling. Is available.

 [0045] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In addition, as the additive in the pharmaceutical composition, one that conforms to official standards such as JP, Pharmaceutical Additive Standard 2003, Japanese Pharmacopeia Standard 1997, or a reagent was used.

 Example

 [Example 1]

2 mL of a 200 mg / mL glibenclamide DMSO solution was added to 38 mL of a 10.5 mg / mL SDS aqueous solution, stirred, and then immediately put into a nanomizer, followed by lOmin treatment to obtain a fine particle dispersion. This dispersion was dialyzed with an lOmg / mL aqueous SDS solution to remove DMSO to obtain a concentrated dispersion (hereinafter referred to as dispersion A). A-CD 1350mg and 12.5mL of purified water were added per 7.5m of dispersion A and mixed (solids concentration 7.5% = darivenclamide in dispersion) SDS and α-CD concentrations). This solution was spray-dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air: 1 kgf / cm ² , liquid feed) Speed: 7mL / min). The composition containing fine particles was spray-dried. As a result, a fine particle-containing composition containing 5 parts by mass of daribenclamide, 5 parts by mass of SDS, and 90 parts by mass of a-CD per 100 parts by mass of the fine particle-containing composition was obtained.

 (Example 2 to Example 3)

 In the production method of Example 1, instead of a-CD, j8-cyclodextrin (Nippon Food Processing Co., Ltd., hereinafter abbreviated as j8-CD) or γ-cyclodextrin (Japan Food Processing Co., Ltd., hereinafter) , And abbreviated as γ-CD), a composition containing fine particles containing | 8-CD (Example 2) and a composition containing fine particles containing γ-CD (Example 3) were obtained. .

 [0048] (Comparative Examples 1 to 6, Control Example 1)

A fine particle-containing composition was obtained using the saccharides listed in Table 1. A fine particle-containing composition containing lactose of Comparative Example 1 was prepared according to the method described in Example 1, and was obtained at a spray drying temperature of 175 ° C. The fine particle-containing composition containing D-mannthol of Comparative Example 2 was obtained according to the method described in Example 1. In addition, the composition containing fine particles containing erythritol, sucrose, and trehalose was prepared by adding 1 mL of 200 mg / mL glibenclamide DMSO solution in 39 mL of 5.1 mg / mL SDS aqueous solution, and then quickly charging it into the Nanomizer. A fine particle dispersion was obtained by treating for lOmin. This dispersion was dialyzed with a 5 mg / mL aqueous SDS solution to remove DMSO, and a concentrated dispersion (hereinafter referred to as dispersion B) was obtained. For each 15 mL of dispersion B, 1350 mg of each saccharide and 5 mL of purified water were added and mixed (solid content concentration 7.5%). Using SD-GB22, this solution was spray-dried at an inlet air temperature of 115 ° C (Comparative Example 3, Comparative Example 5, Control Example 1) or 175 ° C (Comparative Example 4) to obtain a fine particle-containing composition. Obtained (air volume: 0.5 m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed: 7 mL / min). As a result, in the same manner as in Example 1, a fine particle-containing composition containing 5 parts by mass of darribenclamide, 5 parts by mass of SDS, and 90 parts by mass of sugar per 100 parts by mass of the fine particle-containing composition was obtained. Furthermore, instead of erythritol, an attempt was made to prepare using sodium chloride sodium salt, but the fine particles in the dispersion agglomerated and precipitated, and were unable to be spray dried. As a control example 1, as a system without addition of cyclodextrin or saccharide, dispersion B (solid content concentration: 1%) was spray-dried at 115 ° C (air volume: 0.5 m ³ / min, ato mizing air: lkgf / cm ² , liquid feed rate: 7 mL / min), no cyclodextrin! /, fine particle-containing composition (100 parts by weight of composition: 50 parts by weight of darifenclamide, 50 parts by weight of SDS )

[0049] (Test Example 1)

 (Preservation test)

 Each of the fine particle-containing compositions prepared in the above examples or comparative examples was filled in a glass bottle, and the glass bottle was left uncovered in a storage cabinet under an environmental condition of 60 ° C. and 75% (relative humidity). Stored for a week. The particle size of the fine particles in each fine particle-containing composition was measured before and after storage.

 (Measurement method of average particle size)

 The fine particle-containing composition was added to purified water and stirred to obtain a solution in which fine particles of poorly soluble drug were dispersed. The concentration of daribenclamide in the measurement dispersion at this time was 0.25 mg / mL. The particle diameter was measured by the dynamic light scattering method using ELS-8000 (Otsuka Electronics Co., Ltd.), and the cu mulant diameter was adopted as the average particle diameter. From the measured value, the change rate of the average particle diameter after storage with respect to the initial average particle diameter was obtained.

[0050] The results are shown in Table 1. The fine particles of daribenclamide in dispersion A had an average particle size of 205.8 ηm. In dispersion B, the average particle size was 198.6 nm. Surprisingly, the fine particle-containing composition containing cyclodextrin has a particle size change due to spray drying, and even though it has been stored at high humidity after pulverization, the particle size change of darivenclamide fine particles over time is It was almost unacceptable.

The control saccharide was almost equivalent to the system containing cyclodextrin after spray drying, but the average particle size after pulverization increased, and even in the case of D-mannthol, which had the least change, 1. Increased more than 4 times. In the control example in which no cyclodextrin or saccharide was added, the average particle size became 1000 or more by spray drying. Furthermore, the average particle size increased in the storage test. Therefore, it has been found that the cyclic oligosaccharide contributes to the aggregation of fine particles of poorly soluble drugs and the suppression of crystal growth during spray drying in the drying process or during storage after production. In particular, compared to other saccharides, the change in particle size of solidified particles, that is, aggregation and crystal growth in a solid state can be significantly suppressed. It has been confirmed that it has an effect.

[0051] [Table 1]

 Mixing ratio: glibenclamide / SDS / sugar = 5/5/90

 Control example 1 is glibenclamide / SDS / sugar = 50/50/0

[0052] (Example 4)

Dispersion A was prepared by the method described in Example 1. Α-CD 225 mg per 7.5 m of this dispersion A was mixed (solid content concentration 5%). The above solution was spray dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air: lkgf / cm ² , Liquid speed: 7 mL / min). As a result, a fine particle-containing composition containing 20 parts by mass of daribenclamide, 20 parts by mass of SDS, and 60 parts by mass of a-CD per 100 parts by mass of the fine particle-containing composition was obtained.

[0053] (Comparative Example 7)

 In the method of Example 4, D-mannthol was used instead of a-CD. In Test Example 1, D-mannthol most inhibited the change in the average particle size of the fine particles among saccharides other than CDs.

[Test Example 2]

A storage test was conducted in the same manner as in Test Example 1, and the average particle size of the slightly soluble drug fine particles was measured. The results are shown in Table 2. Even in solidified microparticle-containing compositions containing drugs at high concentrations, cyclic oligosaccharides change in particle size due to aggregation and crystal growth over time. It was effective in suppressing crystallization. The average particle size of the fine particles of dispersion A in Example 4 was 214.8 nm.

[0055] [Table 2]

 Mixing ratio: glibenclamide / SDS / sugar = 20/20/60

[Example 5]

Lactose (1275 mg), a-CD (75 mg), and purified water (12.5 mL) were mixed per 7.5 m of the dispersion A described in Example 4 (solid content concentration 7.5%). The above solution was spray dried using SD-GB22 at an inflow air temperature of 175 ° C to obtain a solidified fine particle-containing composition (air volume: 0 • 5m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed: 7mL / min). As a result, a fine particle-containing composition containing 5 parts by mass of darribenclamide, 5 parts by mass of SDS, 5 parts by mass of a-CD, and 85 parts by mass of lactose was obtained per 100 parts by mass of the fine particle-containing composition.

[0057] (Example 6)

Lactose 1200 mg, 0; -ji 015 (^ _§ , 12.5 mL of purified water) and mixed (7.5% solids concentration) per 7.5 m of dispersion A described in Example 4 (The solid content was 7.5%) Using SD-GB22 As a result, 5 parts by mass of darivenclamide, 5 parts by mass of SDS, 10 parts by mass of a-CD, and 100 parts by mass of the fine particle-containing composition were obtained. A fine particle-containing composition containing 80 parts by mass of lactose was obtained.

[0058] (Test Example 3)

 The storage test and the average particle size were measured in the same manner as in Test Example 1. The results are shown in Table 3. Even in a mixed system with other excipients such as lactose, cyclic oligosaccharides were effective in suppressing the change in particle size due to aggregation and crystal growth over time.

[0059] [Table 3] Average particle size (nm)

 Mixing ratio Change rate (%)

 After initial save

 Comparative Example 1 5/5/0/90 210. 7 885. 5 320%

 Example 5 5/5/5/85 218. 5 532. 5 144%

 Example 6 5/5/10/80 227. 2 301. 4 33%

 Mixing ratio: Dariven clamide / SDS / oc-CD / lactose

[Example 7]

A 20 mg / mL aqueous SDS solution was charged with 2000 mg of darivenclamide and stirred, and then quickly put into a nanomizer and treated for 10 minutes to obtain a fine particle dispersion (hereinafter referred to as dispersion C). Disperse C per 2m of dispersion C, 1860mg of H-CD and 28mL of purified water (solid concentration 6.7%) o Spray drying of the above solution using SD-GB22 at an inlet air temperature of 115 ° C Thus, a fine particle-containing composition was obtained (air volume: 0.5 m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed: Ί mL / min) ₀ As a result, per 100 parts by mass of the fine particle-containing composition, darivenclamide 5 A fine particle-containing composition containing 2 parts by mass of SDS, 2 parts by mass of SDS, and 93 parts by mass of a-CD was obtained.

[Example 8]

860 mg of a-CD and 13 mL of purified water were added per 2 m of dispersion C described in Example 7 and mixed (solid content concentration 6.7%). This solution was spray-dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed) : 7 mL / min). As a result, a fine particle-containing composition containing 10 parts by mass of darivenclamide, 4 parts by mass of SDS, and 86 parts by mass of a-CD per 100 parts by mass of the fine particle-containing composition was obtained.

[0062] (Example 9)

A 2-CD 360 mg and purified water 5.5 mL were added to 2 m of the dispersion C described in Example 7 and mixed (solid content concentration 6.7%). This solution was spray dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed: 7 mL / min). As a result, a fine particle-containing composition containing 20 parts by mass of darivenclamide, 8 parts by mass of SDS, and 72 parts by mass of a-CD per 100 parts by mass of the fine particle-containing composition was obtained.

[0063] (Example 10) Α-CDllOmg and 1.75 mL of purified water were mixed per 2 m of dispersion C described in Example 7 (solid content concentration 6.7%). The above solution was spray dried using SD-GB22 at an inlet air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed) : 7 mL / min). As a result, a fine particle-containing composition containing 40 parts by mass of darribenclamide, 16 parts by mass of SDS, and 44 parts by mass of a-CD per 100 parts by mass of the fine particle-containing composition was obtained.

[0064] (Control Example 2)

 Dispersion C described in Example 7 (7.0% as the solid content concentration) was directly subjected to spray drying using SD-GB22 at an inlet air temperature of 115 ° C. to obtain a fine particle-containing composition (air volume: 0.5 m I min, atomizing air: lkgf / cm, dredging speed: 7mL / min).

[0065] (Test Example 4)

 The storage test and the average particle size were measured in the same manner as in Test Example 1. The results are shown in Table 4. Although not shown in the table, the average particle size of the fine particles in dispersion C was 675.6 nm. Compared with Control Example 2 in which no CD was added, it was confirmed that the example in which CD was added suppressed the change in particle diameter due to spray drying even at a high drug concentration of 40%. In particular, when the drug concentration is 5 to 20%, cyclic oligosaccharides are effective in suppressing the change in particle size due to aggregation and crystal growth over time even in a solid composition containing fine particles containing a drug. It was confirmed that there was. In addition, in this test, the poorly soluble drug was used as a good solvent in the same manner as in the fine particle-containing composition produced using Dispersion A or Dispersion B prepared by dissolving a poorly soluble drug in a good solvent in the mixing step. Even when Dispersion C, which was mixed and refined without dissolving, was used, the average particle size of the drug fine particles was slightly increased, but a stable micron-containing composition could be obtained.

[0066] [Table 4] Average particle size (nm)

 Content ratio Change rate (%)

 After initial save

 Example 7 5/2/93 554. 5 620. 3 12% Example 8 10/4/86 562. 0 692. 8 23% Example 9 20/8/72 564. 2 633. 5 12% Example 10 40/16/44 576. 2 1325. 2 130% Control example 2 71/29/0 624. 5 7142. 6 1044% Content ratio: Glibenclami / SDS / a-CD

[Example 11]

 100 mg of the fine particle-containing composition obtained in Example 1, 400 mg of lactose, 15 mg of hydroxypropyl cellulose (HPC-L, Nippon Soda) and 55 L of 10% a-CD aqueous solution were mixed in a mortar. This mixture was dried at 60 ° C. for 2 hours, and then granulated by forcibly sieving through a 16 mesh sieve to obtain granules containing darivenclamide fine particles and ex-CD.

 [Example 12]

 100 mg of the fine particle-containing composition obtained in Example 2, 400 mg of lactose, 11.5 mg of HPC-L, and 54 L of 7% HPC-L aqueous solution were mixed in a mortar. The mixture was dried at 60 ° C. for 2 hours and then granulated by forced sieving through a 16 mesh sieve to obtain granules containing darivenclamide fine particles and β-CD.

 [0069] (Example 13)

 The fine particle-containing composition lOOmg obtained in Comparative Example 1, lactose 310 mg, a-CD 90 mg, HPC-L 15 mg, and 10% a-CD aqueous solution 55 L were mixed in a mortar. The mixture was dried at 60 ° C. for 2 hours, and then granulated by forcibly sieving through a 16 mesh sieve to obtain granules containing fine particles of darifenclamide and ex-CD.

 [0070] (Comparative Example 8)

 100 mg of the fine particle-containing composition obtained in Comparative Example 1, 400 mg of lactose, 15 mg of HPC-L and 50 / z L of purified water were mixed in a mortar. This mixture was dried at 60 ° C. for 2 hours, and then granulated by forced sieving through a 16 mesh sieve to obtain a koji granule containing darivenclamide fine particles and lactose, but not containing CDs.

[Comparative Example 9] 100 mg of the fine particle-containing composition obtained in Comparative Example 1, 400 mg of lactose, 11.5 mg of HPC-L, and 54 L of 7% HPC-L aqueous solution were mixed in a mortar. This mixture was dried at 60 ° C. for 2 hours, and then granulated by forced sieving through a 16 mesh sieve to obtain granules containing darivenclamide fine particles and lactose, and containing no CDs.

[0072] (Test Example 5)

 A storage test was conducted under the same conditions as in Test Example 1. The average particle size was measured in the same manner as in Test Example 1. The results are shown in Table 5. As a result, the granule prepared using the solidified fine particle-containing composition has suppressed particle size changes caused by aggregation of fine particles of poorly soluble drug and crystal growth even after the granulation operation. Turned out to be. Furthermore, surprisingly, in Examples 11-13, which contain cyclic oligosaccharides in the formulation, the increase in particle size due to aggregation and crystal growth over time was almost completely suppressed. Of particular note is Example 13, which confirms that adding cyclic oligosaccharides during the granulation stage is effective in suppressing the aggregation of nanoparticles over time and the change in particle size due to crystal growth. It was done. In other words, not only when the cyclic oligosaccharide is added to the fine particle dispersion before drying, but also when it is added to a solidified mixture after drying (such as the first mixture in the third embodiment). It was confirmed that the increase in the particle size of the slightly soluble drug fine particles can be prevented. This result demonstrates that the effect of the cyclic oligosaccharide in the present invention has a different action from the so-called inclusion of a poorly soluble drug.

[0073] [Table 5]

[0074] (Control Example 3) 2 ml of DMSO solution of 200 mg / mL darribenclamide was placed in 38 ml of purified water, stirred, and then immediately charged into Nanomizer for nanomizer treatment. However, under the preparation conditions where SDS was not used, the nanosuspension could not be prepared because the channel of the nanomizer was blocked. In Control Example 2 containing a surfactant, a fine particle dispersion containing fine particles of 1000 ° or less and a fine particle-containing composition after drying were obtained. The presence of surfactant was confirmed to be important during wet grinding.

[0075] (Test Example 6)

 In order to confirm the influence of cyclodextrin, the concentration ratio of SDS and cyclodextrin was changed, and a dispersion containing fine particles of darifenclamide was prepared by the following method, and the average particle size was compared. The average particle size was measured according to the same method as in Test Example 1.

[0076] (Preparation method)

 A dispersion containing fine particles is obtained by adding 2 ml of DMSO solution of 200 mg / ml darribenclamide to 38 ml of an aqueous solution containing 200 mg of SDS and 169 mg of a-CD, stirring it, and then immediately putting it into the nanomizer and processing for lOmin. It was. Similarly, 2 ml of a 200 mg / ml glibenclamide solution in DMSO was added to 38 ml of an aqueous solution containing 337 mg, 675 mg, 1350 mg, and 2700 mg, respectively, to obtain a fine particle-containing dispersion.

[0077] (Test results)

 Figure 5 shows the test results. As a result, by increasing the a-CD concentration relative to SDS at the time of preparation of the fine particle-containing dispersion, the average particle diameter changes rapidly when the molar ratio of SDS to α-CD is around 1: 1 to 1: 2. Was confirmed. This indicates that the surface-active ability of SDS is reduced, suggesting the formation of inclusion bodies between SDS and a-CD. This means that the average particle size is smaller! In order to obtain the soot particles, it was confirmed that it is preferable to include the surfactant present in excess by adding cyclodextrin after the dispersion containing the drug and the surfactant is refined. Of course, the object of the present application can be achieved even if cyclodextrin is added in advance to a dispersion containing a drug and a surfactant.

 [Test Example 7]

In Test Example 6, it was suggested that the surfactant by cyclodextrin and SDS were included. . Therefore, a solubility measurement test was conducted under the coexistence of the two, and inclusion claws were examined. [0079] (Test method)

 To 4 ml of an aqueous solution containing a-CD and SDS, 20 mg of darifenclamide was added and stirred at room temperature for 3 days or more. The above solution was filtered using a Millex-HV filter (manufactured by Millipore) having a pore size of 0.45 μm, and the darivenclamide concentration in the filtrate was measured by HPLC using an Unison UK-C18 column (manufactured by Imtakt).

[0080] (Test result)

 Figure 6 shows the solubility of darifenclamide versus SDS concentration under various concentrations of CD. When a-CD was O.OmM, it was confirmed that there was an inflection point indicating the minimum solubility for the SDS concentration in the system supplemented with a-CD. In the case of showing such a solubility curve diagram, both indicate that an inclusion body is formed. Moreover, the inflection point corresponds to α-CDZSDS molar specific power ~ 2, which is consistent with the result of Fig. 5.

[0081] (Example 14)

送液速度： 7mL/min)。この結果、微粒子含有組成物 100質量部あたり、 ダリベンクラミド 5質量部、 SDS 5質量部、ひ- CD 90質量部を含む微粒子含有組成 物を得た。この微粒子含有組成物中の微粒子の平均粒子径は、 314.7nm (175°C)で あった。噴霧乾燥温度が、 115°C (その他の条件は同じ)の実施例 1と比較し、やや大 きな粒子サイズであった力 lOOOnm以下の微細な粒子を含む微粒子含有組成物を 得ることができた。 Dispersion A was prepared according to the method described in Example 1, and 17.5 mg of a-CD and 12.5 mL of purified water were added and mixed per 7.5 m of dispersion A. At this time, the average particle size of the fine particles in the fine particle-containing dispersion of the drug was 222.8 nm. This solution was spray-dried using SD-GB22 at an inflow air temperature of 175 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air:

(Liquid feeding speed: 7 mL / min). As a result, a fine particle-containing composition containing 5 parts by mass of darribenclamide, 5 parts by mass of SDS, and 90 parts by mass of CD per 100 parts by mass of the fine particle-containing composition was obtained. The average particle size of the fine particles in this fine particle-containing composition was 314.7 nm (175 ° C.). Compared with Example 1 having a spray drying temperature of 115 ° C (other conditions are the same), a fine particle-containing composition containing fine particles with a force lOOOnm or less which was a slightly larger particle size can be obtained. It was.

 [0082] (Example 15)

After preparing dispersion A by the method described in Example 1, 50 mg of | 8-CD 13 and 92.5 ml of purified water were added per 7.5 m of dispersion A and mixed (solid content concentration 1.5%). At this time, drug fine particles The average particle size of the fine particles in the dispersed liquid was 222.8 nm. Using SD-GB22, this solution was spray-dried at an inlet air temperature of 115 C, an air volume of 0.5 m ³ / min atomizing air: lkgf / cm ² , and a liquid feed rate of 7 ml / min to obtain a fine particle-containing composition. Obtained. As a result, a fine particle-containing composition containing 5 parts by mass of daribenclamide, 5 parts by mass of SDS, and 90 parts by mass of | CD-CD per 100 parts by mass of the fine particle-containing composition was obtained. The average particle size of the fine particles in this composition was 407.9 ηm. Compared with Example 2 in which the solid content concentration in the fine particle-containing dispersion was 7.5%, a fine particle-containing composition containing fine particles having a slightly larger particle size and a force of lOOOnm or less was obtained.

[0083] (Example 16)

2mg / mL SDS aqueous solution of mefenamic acid (2- (2,3-Dimethylphenylamino) benzoic acid, almost insoluble in water, Wako Pure Chemicals) in 40mL, add lOOmg and stir, then quickly add to nanomizer, lOmin A fine particle dispersion (hereinafter referred to as “dispersion X”) was obtained by performing the intermediate treatment. At this time, the average particle size of the drug fine particles in dispersion Z was 609. 40 mg of α-CD was added per X lm dispersion and mixed (solid content concentration 4.4%). The above solution was spray-dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air flow 0.5 m ³ / min atomizing air: lkgf / cm ² , liquid feeding speed: 7 mL / min). As a result, a fine particle-containing composition containing 5.6 parts by mass of mefenamic acid, 4.5 parts by mass of SDS, and 89.9 parts by mass of a-CD per 100 parts by mass of the fine particle-containing yarn and composition was obtained.

[0084] (Comparative Example 10)

40 mg of D-manntol was added to each X lm of the dispersion prepared in Example 16 and mixed (solid content concentration 4.4%). The above solution was spray-dried using SD-GB22 at an inlet air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min atomizing air lkgf / cm ² liquid feed rate: 7 mL / min). As a result, per 100 parts by mass of the fine particle-containing composition, mefenamic acid

A fine particle-containing composition containing 5.6 parts by mass, 4.5 parts by mass of SDS, and 89.9 parts by mass of D-manntol was obtained.

[0085] (Example 17)

Spironoratatone (7 a-Acetylsulfanyl-3-oxo-17 a-pr egn-4- ene-21,17 j8-carbolactone, Wako Pure Chemicals, almost insoluble in water) in 40 mL of 5 mg / mL SDS aqueous solution After stirring, the mixture was quickly put into the nanomizer and treated for lOmin to obtain a fine particle dispersion (hereinafter referred to as dispersion Y). At this time, the average particle diameter of the drug fine particles in dispersion Z was 562 nm. This dispersion Y lm was mixed with 42.5 mg of a-CD (solid content concentration 5%). The above solution was spray dried using SD-GB22 at an inflow air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air: lkgf / cm ² , liquid feeding speed) : Ί mL / min) ₀ As a result, fine particle-containing composition 100 parts by weight per Supironorataton 5 parts by weight, SDS 10 parts by weight, to obtain a fine particle-containing composition comprising a -CD 85 parts by weight.

[0086] (Test Example 8)

 The storage test and the average particle size were measured in the same manner as in Test Example 1. However, the drug concentration O.lmg / ml at the time of average particle measurement was adopted. The results are shown in Table 6. From Table 6, comparison of Example 16 and Comparative Example 10 using mefenamic acid as the drug and SDS as the surfactant showed a significant increase in particle size when stored under high humidity by adding a-CD. It is clear that this is suppressed. Further, in Example 17 using spironolatone as the drug and SDS as the surfactant, the initial particle size after solidification was 756.1 ° C, and the particle size after storage was 826.9. The rate of change was 9%, and almost no increase in particle size was observed. The above results are surprising data showing that the effect of suppressing the increase in particle size of a-CD can be obtained even with a combination of various drugs and surfactants.

[0087] [Table 6]

 Mixing ratio: Mef I Namic acid / SDS / Sugar = 5.6 / 4/4 5 / 89.9

[0088] 2 mg of DMSO solution of 200 mg / mL glibenclamide was added to 38 mL of 4.2 mg / mL SDS aqueous solution, and after stirring, it was immediately put into a nanomizer and treated for lOmin to obtain a fine particle dispersion. This dispersion was dialyzed with a 4 mg / mL aqueous SDS solution to remove DMSO to obtain a dispersion (hereinafter referred to as dispersion D). At this time, the average particle size of the drug fine particles in dispersion Z was 207 nm. Add 186 mg of a-CD and 1.67 mL of purified water to each dispersion of D lm. Mixed (solid content concentration 7.5%). This solution was spray dried using SD-GB22 at an inlet air temperature of 115 ° C to obtain a fine particle-containing composition (air volume: 0.5 m ³ / min, atomizing air: 1 kgf / cm ² , liquid feed) Speed: 7mL / min). The composition containing fine particles was spray-dried. Result of measurement of darivenclamide content in fine particle-containing composition by high performance liquid chromatography (detection wavelength 230 nm) using ODS column with 0.1N potassium dihydrogen phosphate aqueous solution / acetonitrile = 9/11 mixed solution as mobile phase Was 4.15 wt%. After mixing 2318 mg of the above fine particle-containing composition with 5282 mg of D-mannthol, 1000 mg of corn starch, 500 mg of low-substituted hydroxypropyl cellulose, 300 mg of hydroxypropylcellulose, and an appropriate amount of purified water in a calorie mortar, It heat-dried using the tank. Low-substituted hydroxypropylcellulose (455 mg) and magnesium stearate (91 mg) were added to and mixed with 8554 mg of the granules after drying. 130 mg of the above mixture was collected and tableted using Autograph AG5000A (Shimadzu Corporation) to obtain a tablet with a diameter of 7 mm containing 1.25 mg of darivenclamide.

[0089] (Comparative Example 11)

 Glybenclamide 96.2mg, a-CD 2571.3mg, D-manthol 4894.0mg, S DS 38.5mg, corn starch 1000mg, low-substituted hydroxypropylcellulose 500mg, hydroxypropylcellulose 300mg, in a mortar with appropriate amount of purified water After mixing in, it was dried by heating using a thermostatic bath. 455 mg of low-substituted hydroxypropylcellulose and 91 mg of magnesium stearate were added to and mixed with 8554 mg of the granules after drying. 130 mg of the above mixture was collected and tableted using an autograph AG5000A (Shimadzu Corporation) to obtain a tablet having a diameter of 7 mm containing 1.25 mg of darifenclamide.

[0090] (Test Example 9)

Using Example 18, a storage test and an average particle size measurement were carried out in the same manner as in Test Example 1. In this study, the storage conditions were 60 ° C 75% RH, 1 week, and 1 month. In addition, since the tablets contained insoluble additives, the average particle size was measured after filtration using a filter having a pore size of 5 m. As a result, the average particle size of darivenclamide fine particles in the tablets immediately after manufacture was 360.3 nm, 404.7 nm in 1 week after storage, and 403.3 in 1 month after storage. The subsequent average particle size change rate was 11-12%. By the compression molding process using the fine particle-containing composition according to the present invention. Even in the processed tablet, the drug microparticles were stable. From this test, it was confirmed that the fine particles of the present invention were stable without being affected by the compression process, excipients or storage conditions during production.

[0091] (Test Example 10)

 The dissolution test was performed on Example 18 and Comparative Example 11. For Example 18, a dissolution test was performed using the sample subjected to the storage test of Test Example 7. The dissolution test was performed according to the dissolution test method of the 14th Japanese Pharmacopoeia, using water as the test solution at a paddle rotation speed of 50 rpm. The sample solution collected over time was filtered using a Millipore PVDF filter (pore size: 0.22 m), and then HPLC analysis was performed to calculate the concentration of darivenclamide in the sample solution collected. The elution rate was determined. HPLC analysis was performed using an ODS column under the conditions of mobile phase: 0.1N aqueous potassium dihydrogen phosphate / acetonitrile = 9/11 mixture, detection wavelength: 230 nm. As a result, the drug elution improvement effect was confirmed in Example 19 in which the drug was blended as fine particles, compared to Comparative Example 12 in which the drug was blended without miniaturization (see FIG. 7). In addition, regarding Example 19, it was confirmed that the elution profile hardly changed before and after storage (see FIG. 8). Therefore, it was confirmed that the fine particle-containing composition according to the present invention can improve the dissolution property of a poorly soluble drug, and that the drug dissolution from the preparation is stable without change due to storage.

 Industrial applicability

[0092] According to the present invention, in the technique of atomizing a poorly soluble drug by wet pulverization using a surfactant, a suspension containing fine particles of the poorly soluble drug is further dried by using a cyclic oligosaccharide. In the composition and the dried composition, aggregation and crystal growth over time of the fine particles of the hardly soluble drug can be suppressed. Furthermore, according to the present invention, it is possible to provide a fine particle-containing composition in which fine particles of a poorly soluble drug are present physically and stably without being affected by the storage environment such as temperature and humidity. Therefore, according to the present invention, it is possible to simply blend fine particles of a poorly soluble drug into tablets and capsules that are widely used in oral preparations, or time-adjustable dry syrups that can be redispersed in water. it can. Furthermore, according to the present invention, the poorly soluble drug can be orally administered while maintaining the size as fine particles, so that the absorption of the hardly soluble drug is promoted and the bioavailability is increased. It is possible to provide a pharmaceutical composition with excellent medication compliance, such as increasing the dose or reducing the amount of drug. Furthermore, since the fine particle-containing composition of the present invention or a pharmaceutical composition containing the same is excellent in storage stability, it can be transported and distributed as a premix raw material for pharmaceuticals or as a pharmaceutical and can be widely spread immediately. .

Brief Description of Drawings

FIG. 1 is a flowchart of a production process showing a first embodiment of the present invention.

FIG. 2 is a flowchart of a manufacturing process showing a second embodiment in the present invention.

FIG. 3 is a flowchart of a manufacturing process showing a third embodiment in the present invention.

FIG. 4 is a flowchart of a manufacturing process showing a fourth embodiment in the present invention.

FIG. 5 is a graph showing changes in the average particle diameter of fine particles with respect to the oc-CD / SDS molar ratio in a fine particle-containing dispersion of darifenclamide.

 FIG. 6 is a graph showing the solubility of darifenclamide in the presence of a-CD and SDS.

FIG. 7 shows the dissolution profile of a tablet containing fine particles of darifenclamide.

FIG. 8 is a diagram showing dissolution profiles before and after a storage test of tablets containing fine particles of darifenclamide.

Claims

The scope of the claims  [1] A composition containing fine particles of a poorly soluble drug, a surfactant and a cyclic oligosaccharide, wherein the fine particles have an average particle size of 50 to lOOOnm.  [2] (I) a mixing step of mixing a poorly soluble drug, a surfactant and a poor solvent to obtain a mixed solution; (II) a refining step of refining the mixed solution with a wet disperser to obtain a fine particle dispersion; The fine particle-containing product according to claim 1, wherein the fine particle-containing product is produced by a production method comprising (iv) an addition step of adding a cyclic oligosaccharide to the fine particle dispersion, and (IV) a drying step of drying the fine particle dispersion containing the cyclic oligosaccharide. Composition.  [3] (I) A mixing step in which a poorly soluble drug, a surfactant, a poor solvent and a cyclic oligosaccharide are mixed to obtain a mixed solution. (Ii) The mixed solution is refined with a wet disperser to obtain a fine particle dispersion. 2. The fine particle-containing composition according to claim 1, wherein the fine particle-containing composition is produced by a production method comprising a refinement step and (III) a drying step of drying the fine particle dispersion.  [4] (I) A mixing step in which a poorly soluble drug, a surfactant and a first poor solvent are mixed to obtain a mixed solution. (I) The mixed solution is refined with a wet disperser to obtain a fine particle dispersion. (III) a first drying step for obtaining a first mixture by drying the fine particle dispersion, and (IV) adding a cyclic oligosaccharide and a second poor solvent to the first mixture. The fine particle-containing composition according to claim 1, which is produced by an addition step for obtaining a second mixture, and (V) a production method comprising a second drying step for drying the second mixture.  [5] The fine particle-containing composition according to any one of [2] to [4], wherein in the mixing step, a poorly soluble drug solution in which a poorly soluble drug is dissolved in a good solvent is mixed.  [6] The method according to any one of claims 2 to 5, further comprising a concentration step of concentrating the fine particle dispersion or the fine particle dispersion containing the cyclic oligosaccharide, prior to the drying step or the first drying step. The fine particle-containing composition described.  7. The fine particle-containing composition according to any one of claims 2 to 6, wherein the drying step or the first drying step is a drying step using a spray drying method. [8] The fine particle-containing composition according to any one of [2] to [7], wherein the wet disperser is a homogenizer. [9] The fine particle-containing composition according to any one of [1] and [8], wherein the cyclic oligosaccharide is encapsulated with the surfactant. 10. The fine particle-containing composition according to any one of claims 1 to 9, wherein the cyclic oligosaccharide is a cyclodextrin. [11] The fine particle-containing composition according to any one of [1] to [10], wherein the surfactant is a surfactant having a hydrocarbon chain having 4 or more carbon atoms. [12] The fine particle-containing composition according to any one of claims 1 to 11, wherein the hardly soluble drug is 0.1 to 40 parts by weight with respect to 100 parts by weight of the fine particle-containing composition. [13] A solid pharmaceutical composition comprising the fine particle-containing composition according to any one of claims 1 to 13.  14. The solid pharmaceutical composition according to claim 13, wherein the solid pharmaceutical composition is selected from the group having tablet, granule, capsule and dry syrup strength.  [15] (I) A mixing step of mixing a poorly soluble drug, a surfactant and a poor solvent to obtain a mixed solution, (II) a refining step of refining the mixed solution with a wet disperser to obtain a fine particle dispersion, (Ii) A method for producing a fine particle-containing composition comprising an addition step of adding a cyclic oligosaccharide to the fine particle dispersion and (IV) a drying step of drying the fine particle dispersion containing the cyclic oligosaccharide.  [16] (I) A mixing step in which a poorly soluble drug, a surfactant, a poor solvent and a cyclic oligosaccharide are mixed to obtain a mixed solution, (ii) the mixed solution is refined with a wet disperser to obtain a fine particle dispersion. A method for producing a fine particle-containing composition, which comprises a fine step and (III) a drying step of drying the fine particle dispersion.  [17] (I) A mixing step in which a poorly soluble drug, a surfactant and a first poor solvent are mixed to obtain a mixed solution. (I) The mixed solution is refined with a wet disperser to obtain a fine particle dispersion. (III) a first drying step for obtaining a first mixture by drying the fine particle dispersion, and (IV) adding a cyclic oligosaccharide and a second poor solvent to the first mixture. An addition step for obtaining a second mixture; (V) a method for producing a fine particle-containing composition comprising a second drying step for drying the second mixture. [18] The production of the fine particle-containing composition according to any one of claims 15 to 17, wherein in the mixing step, a poorly soluble drug solution in which a poorly soluble drug is dissolved in a good solvent is mixed. Method.  [19] The method according to any one of claims 15 to 18, further comprising a concentration step of concentrating the fine particle dispersion or the fine particle dispersion containing the cyclic oligosaccharide, prior to the drying step or the first drying step. A method for producing the described fine particle-containing composition. 20. The method for producing a fine particle-containing composition according to any one of claims 15 to 19, wherein the drying step or the first drying step is a drying step using a spray drying method. 21. The method for producing a fine particle-containing composition according to any one of claims 15 to 20, wherein the wet disperser is a homogenizer. [22] The method for producing a fine particle-containing composition according to any one of [15] to [21], wherein in the addition step, the cyclic oligosaccharide includes the surfactant.  23. The method for producing a fine particle-containing composition according to any one of claims 15 to 22, wherein the cyclic oligosaccharide is cyclodextrin. 24. The method for producing a fine particle-containing composition according to any one of claims 15 to 23, wherein the surfactant is a surfactant having a hydrocarbon chain having 4 or more carbon atoms. [25] The method for producing a fine particle-containing composition according to any one of claims 15 to 24, wherein the hardly soluble drug is 0.1 to 40 parts by mass with respect to 100 parts by mass of the fine particle-containing composition.